Now Zorn is among the small army of researchers trying to unlock cures, or at least decent treatments, for Alzheimer's and other brain disorders.
No one knows exactly what Alzheimer's is, or why, precisely, some people's brains betray them. The best hypothesis revolves around a protein called amyloid, which shows up in large plaques on the brains of people affected by Alzheimer's, similar to the way plaques form on teeth and in arteries.
Nearly fifteen years ago, researchers at pharmaceutical giant Eli Lilly started working on a drug that would attach itself to amyloid particles and prevent them from binding together into plaques. After screening thousands of compounds, they found one that worked in a petri dish. So they engineered some mice to develop amyloid plaques. The drug worked in the mice, too, and at that point, Lilly's scientists let themselves get their hopes up.
"Those were some amazingly exciting times," says Ron DeMattos, Lilly's chief scientific officer for neurobiologics. "You never could come up with a test that proved us wrong."
They were able to develop a drug that wasn't toxic to humans and could actually be absorbed into the brain—a difficult barrier to overcome, because our brains are excellent at keeping out foreign material.
Along the way, a new genetic mutation was discovered in a small group of people in Iceland who lived long lives and seemed to be shielded from Alzheimer's. The finding made researchers even more confident that amyloid was the right target. To know whether their drug was reducing the amount of amyloid in the brain, though, they had to invent a way to measure the protein. Previously, they could only measure amyloid during autopsies. By 2012, Lilly's scientists had cleared all of those hurdles and were wrapping up Phase 3 clinical trials—the last phase before asking the FDA for approval.
The drug failed. Most people in the trial, which had taken more than two years to conduct, showed no significant improvement.
"I was sitting there listening through the phone, and just hearing the response, and the sheer emotion that came out of what a lot of people term a failure," DeMattos remembers. But he cites that moment as among the best of his career. "In reality, this was one of the very first times that we, and myself as a scientist, thought, 'My gosh, we're really gonna get this beast.' That was just so exhilarating, I can't wait to feel that again."
Although failure is frustrating and expensive, drug hunters say the key to progress is to fail well. A well-designed study that's conducted properly should teach you something, even if the outcome isn't what you wanted. "Some of the greatest insights I've ever had were failures—and some pretty big failures," DeMattos says. "We're going to fail thousands of times."
In this case, the lesson was to start earlier. When Lilly's scientists dug a little deeper into their data, they realized that their drug had produced a decent benefit for trial participants who had "mild" Alzheimer's. Every time they cut the data a different way, they remained convinced they were seeing real progress earlier in the disease.